UC Irvine

Aerobic exercise is well know to promote neuroplasticity and hippocampal memory. More recent studies suggest that early-life exercise (EX) can lead to lasting improvements in hippocampal function; however, the molecular mechanisms of this phenomenon are not understood. Histone post translational modifications (HPTMs) are strong candidates for bridging the gap between environmental experiences and altered gene expression. Epigenetic mechanisms such as HPTMs can be persistent or transient and can have lasting influences on neuronal function. This dissertation investigates epigenetic mechanisms a possible explanation for the effect of EX on memory and develops tools for that investigation. In chapter 2 we develop a mouse model and a novel method for coupling epigenetic information and translating mRNA in hippocampal neurons. A Emx1-Cre2 mouse was crossed with a NuTRAP3 mouse to produce a transgenic line we call Emx1-NuTRAP. This mouse expresses a cassette in hippocampal neurons which labels both the nucleus and ribosomes in a way that allowed us to develop a novel method we call “SIT” (simultaneous isolation of nuclei in targeted cell types (INTACT) and translating ribosomal purification (TRAP)) to isolate both translating mRNA and intact nuclei from the same set of cells. We applied our lab’s EX model to the Emx1-NuTRAP mouse, followed by the SIT method from hippocampal tissue to identify an epigenetic and translational signature of EX as it relates to improved memory (Chapter 3). These data revealed activation of neuroplasticity genes engaged by EX, and implicated critical upstream regulators. Chapter 4 demonstrates that EX-induced epigenetic changes correlate with altered gene expression during consolidation that may underly EX-induced enabled memory. We discovered a distinct set of genes that had new histone PTMs after EX that have altered expression during memory consolidation. This suggests that neuronal chromatin in hippocampus may be “primed” by EX-induced new histone PTMs Finally, Chapter 5 describes a novel method for tracking the individual running of group housed juvenile mice. We constructed an RFID tracking system and correlate it with running using a software we developed in-house. This technique could be used to identify a threshold dose of EX for enabling of memory. Taken together, we lay the foundations for the study of epigenetics as a key underlying mechanism of EX enabled memory and identify candidate mechanisms with novel techniques.